This invention relates to the treatment of pulmonary vasoconstriction and to the treatment of asthma. This invention was made in the course of work supported by the U.S. Government, which has certain rights in the invention.
Asthma is a chronic disease characterized by intermittent, reversible, widespread constriction of the airways of the lungs in response to any of a variety of stimuli which do not affect the normal lung. Estimates of the prevalence of this disease in the U.S. population range from three to six percent.
In attempting to unravel the pathogenesis of asthma, the cellular and biochemical basis (sic) for three important features of the disease have been sought: chronic airway inflammation, reversible airflow obstruction, and bronchial hyperreactivity. Theories have pointed variously to abnormalities in autonomic nervous system control of airway function, in bronchial smooth muscle contractile properties, or in the integrity of the epithelial cell lining as features that distinguish asthmatic from normal airways. . . . Evidence suggests that the normal epithelial lining functions as more than a simple barrier: epithelial cells may produce a relaxing factor that actively maintains airway patency by causing relaxation of smooth muscle. Epithelial desquamation could contribute to bronchial hyperreactivity because a lesser amount of relaxing factor would be produced.
("Asthma", Ch. 14-II in Scientific American Medicine, Vol. 2; Scientific American, Inc.; 1988, p. 2, 4)
Drugs used to treat asthma fall generally into two categories: those which act mainly as inhibitors of inflammation, such as corticosteroids and cromolyn sodium, and those which act primarily as relaxants of the tracheobronchial smooth muscle, such as theophylline and its derivatives, beta-adrenergic agonists, and anticholinergics. Some of these bronchodilators may be administered orally, while others are generally given by intravenous or subcutaneous injection or by inhalation of the drug in an appropriate form, such as aerosolized powder (i.e., delivered in the form of a finely divided solid, suspended in a gas such as air), or aerosolized droplets (delivered in the form of a fine mist). Asthma patients typically self-administer bronchodilator drugs by means of a portable, metered-dose inhaler, employed as needed to quell or prevent intermittent asthma attacks.
Conceptually analogous to the narrowing of the airways of the lung which occurs in an asthma attack, vasoconstriction is a reversible narrowing of blood vessels attributable to contraction of the smooth muscle of the blood vessels. Such vasoconstriction can lead to abnormally high blood pressure (hypertension) in the affected portion of the circulatory system.
The mammalian circulatory system consists of two separate systems, the systemic circuit and the pulmonary circuit, which are pumped in tandem by the left and right sides of the heart, respectively. The pulmonary circulation transports the blood through the lungs, where it picks up oxygen and releases carbon dioxide by equilibrating with the concentrations of oxygen and carbon dioxide gas in the alveoli. The oxygen-rich blood then returns to the left side of the heart, from whence it is distributed to all parts of the body via the systemic circulation.
The systemic circulatory system of an adult human typically has a mean systemic arterial pressure ("SAP") of 80-100 mm Hg, whereas a typical mean pulmonary arterial pressure ("PAP") is approximately 12-15 mm Hg. Normal pulmonary capillary pressure is about 7-10 mm Hg. Considering the interstitial fluid colloid osmotic pressure (14 mm Hg) and the plasma colloid oncotic pressure (28 mm Hg), as well as the interstitial free fluid pressure (1-8 mm Hg), the normal lung has a +1 mm Hg net mean filtration pressure (Guyton, Textbook of Medical Physiology, 6th Ed.; W. B. Saunders Co., Philadelphia, Pa. (1981), p. 295). This nearly balanced pressure gradient keeps the alveoli of a healthy lung free of fluid which otherwise might seep into the lung from the circulatory system.
An elevation of the PAP over normal levels is termed "pulmonary hypertension." In humans, pulmonary hypertension is said to exist when the PAP increases by at least 5 to 10 mm Hg over normal levels; PAP readings as high as 50 to 100 mm Hg over normal levels have been reported. When the PAP markedly increases, plasma can escape from the capillaries into the lung interstitium and alveoli: fluid buildup in the lung (pulmonary edema) can result, with an associated decrease in lung function that can in some cases be fatal.
Pulmonary hypertension may either be acute or chronic. Acute pulmonary hypertension is often a potentially reversible phenomenon generally attributable to constriction of the smooth muscle of the pulmonary blood vessels, which may be triggered by such conditions as hypoxia (as in high-altitude sickness), acidosis, inflammation, or pulmonary embolism. Chronic pulmonary hypertension is characterized by major structural changes in the pulmonary vasculature which result in a decreased cross-sectional area of the pulmonary blood vessels; this may be caused by, for example, chronic hypoxia, thromboembolism, or unknown causes (idiopathic or primary pulmonary hypertension).
Pulmonary hypertension has been implicated in several life-threatening clinical conditions, such as adult respiratory distress syndrome ("ARDS") and persistent pulmonary hypertension of the newborn ("PPHN"). Zapol et al., Acute Respiratory Failure, p. 241-273, Marcel Dekker, New York (1985); Peckham, J. Ped. 93:1005 (1978). PPHN, a disorder that primarily affects full-term infants, is characterized by elevated pulmonary vascular resistance, pulmonary arterial hypertension, and right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale of the newborn's heart. Mortality rates range from 12-50%. Fox, Pediatrics 59:205 (1977); Dworetz, Pediatrics 84:1 (1989). Pulmonary hypertension may also result in a potentially fatal heart condition known as "cor pulmonale", or pulmonary heart disease. Fishman, "Pulmonary Diseases and Disorders" 2nd Ed., McGraw-Hill, New York (1988).
Attempts have been made to treat pulmonary hypertension by administering drugs with known systemic vasodilatory effects, such as nitroprusside, hydralazine, and calcium channel blockers. Although these drugs may be successful in lowering the pulmonary blood pressure, they typically exert an indiscriminate effect, decreasing not only pulmonary but also systemic blood pressure. A large decrease in the systemic vascular resistance may result in dangerous pooling of the blood in the venous circulation, peripheral hypotension (shock), right ventricular ischemia, and consequent heart failure. Zapol (1985); Radermacher, Anaesthesiology 68:152 (1988); Vlahakes, Circulation 63:87 (1981). For example, when intravenous nitroprusside was administered to 15 patients for treatment of acute pulmonary hypertension due to ARDS, mean PAP decreased from 29.6 to 24.2 mm Hg and pulmonary vascular resistance (PVR) decreased by a mean of 32%, but mean systemic arterial pressure was reduced from 89.6 mm Hg to the unacceptably low level of 70 mm Hg (Zapol et al., 1985). Intravenous nitroprusside was not recommended for clinical treatment of pulmonary hypertension, since it "markedly impairs pulmonary gas exchange by increasing Q.sub.VA /Q.sub.T " (the mixing of venous and arterial blood via an abnormal shunt). Radermacher (1988).
Physiological relaxation of blood vessels has been reported to result from the release of a very labile non-prostanoid endothelium-derived relaxing factor (EDRF) by endothelial cells lining the blood vessels. EDRF stimulates the enzyme guanylate cyclase within the vascular smooth muscle, with the resulting increase in cyclic GMP causing relaxation of this muscle, and thereby reversing vasoconstriction. Ignarro et al., Proc. Natl. Acad. Sci. USA 84:9265 (1987) and Palmer et al., Nature 327:524 (1987) identified the vascular smooth muscle relaxation factor released by the endothelium of arteries and veins as nitric oxide ("NO"). NO is also believed to be produced by breakdown of organic nitrates such as nitroprusside and glyceryl trinitrate. Ignarro, Circ. Res. 65:1 (1989); Furchgott, FASEB J. 3:2007 (1989). Higenbottam et al., Ann. Rev. Resp. Dis. Suppl. 137:107 (1988), measured the vasodilatory effects of inhaled NO in seven patients with a chronic condition termed primary pulmonary hypertension. The average PAP of these patients when breathing 40 ppm NO was 56.7 mm Hg, compared to 59.6 mm Hg when breathing air without added NO, a difference of 2.9 mm Hg, or about 6% of the difference (".DELTA.PAP") between the pre-treatment PAP and what would be normal PAP. Higenbottam et al. reported an average 9% reduction in PVR in these patients during inhalation of NO. No corresponding decrease in SAP was observed.
When exposed to oxygen, NO gas is unstable and undergoes spontaneous oxidation to NO.sub.2 and higher oxides of nitrogen. These higher nitrogen oxides are toxic to the lung, and can in high concentrations themselves produce pulmonary edema. NO is "the most rapidly binding ligand to haemoglobin so far discovered." Meyer, Eur. Resp. J. 2:494 (1988). In a dilute aqueous solution exposed to oxygen, dissolved NO has a half life of less than 10 seconds due to rapid oxidation to inorganic nitrite and nitrate. Ignarro, FASEB J. 3:31 (1989). The Occupational Safety and Health Administration (OSHA) has set the time-weighted average inhalation limit for NO at 25 ppm for 10 hours. "NIOSH Recommendations for Occupational Safety and Health Standards," Morbidity and Mortality Weekly Report, Vol. 37, No. S-7, p. 21 (1988).